Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Hepatic insulin resistance directly promotes formation of cholesterol gallstones

Abstract

Despite the well-documented association between gallstones and the metabolic syndrome1,2, the mechanistic links between these two disorders remain unknown. Here we show that mice solely with hepatic insulin resistance, created by liver-specific disruption of the insulin receptor (LIRKO mice)3 are markedly predisposed toward cholesterol gallstone formation due to at least two distinct mechanisms. Disinhibition of the forkhead transcription factor FoxO1, increases expression of the biliary cholesterol transporters Abcg5 and Abcg8, resulting in an increase in biliary cholesterol secretion. Hepatic insulin resistance also decreases expression of the bile acid synthetic enzymes, particularly Cyp7b1, and produces partial resistance to the farnesoid X receptor, leading to a lithogenic bile salt profile. As a result, after twelve weeks on a lithogenic diet, all of the LIRKO mice develop gallstones. Thus, hepatic insulin resistance provides a crucial link between the metabolic syndrome and increased cholesterol gallstone susceptibility.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: LIRKO mice are susceptible to cholesterol gallstone formation.
Figure 2: LIRKO mice show quantitative and qualitative defects in bile acid synthesis on a chow diet.
Figure 3: Biliary cholesterol content is increased in LIRKO mice, promoting supersaturated bile.
Figure 4: Insulin regulates Abcg5 and Abcg8 expression through FoxO1.

Similar content being viewed by others

References

  1. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection. Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106, 3143–3421 (2002).

  2. Diehl, A.K. Cholelithiasis and the insulin resistance syndrome. Hepatology 31, 528–530 (2000).

    Article  CAS  Google Scholar 

  3. Michael, M.D. et al. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol. Cell 6, 87–97 (2000).

    Article  CAS  Google Scholar 

  4. Everhart, J.E., Khare, M., Hill, M. & Maurer, K.R. Prevalence and ethnic differences in gallbladder disease in the United States. Gastroenterology 117, 632–639 (1999).

    Article  CAS  Google Scholar 

  5. Sandler, R.S. et al. The burden of selected digestive diseases in the United States. Gastroenterology 122, 1500–1511 (2002).

    Article  Google Scholar 

  6. Osler, W. The Principles and Practice of Medicine 432 (D. Appleton and Company, New York, 1892).

    Google Scholar 

  7. Biddinger, S.B. & Kahn, C.R. From mice to men: insights into the insulin resistance syndromes. Annu. Rev. Physiol. 68, 123–158 (2006).

    Article  CAS  Google Scholar 

  8. Biddinger, S.B. et al. Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis. Cell Metab. 7, 125–134 (2008).

    Article  CAS  Google Scholar 

  9. Heuman, D.M. Quantitative estimation of the hydrophilic-hydrophobic balance of mixed bile salt solutions. J. Lipid Res. 30, 719–730 (1989).

    CAS  PubMed  Google Scholar 

  10. Moschetta, A., Bookout, A.L. & Mangelsdorf, D.J. Prevention of cholesterol gallstone disease by FXR agonists in a mouse model. Nat. Med. 10, 1352–1358 (2004).

    Article  CAS  Google Scholar 

  11. Kok, T. et al. Enterohepatic circulation of bile salts in farnesoid X receptor–deficient mice: efficient intestinal bile salt absorption in the absence of ileal bile acid–binding protein. J. Biol. Chem. 278, 41930–41937 (2003).

    Article  CAS  Google Scholar 

  12. Chen, Q., Amaral, J., Biancani, P. & Behar, J. Excess membrane cholesterol alters human gallbladder muscle contractility and membrane fluidity. Gastroenterology 116, 678–685 (1999).

    Article  CAS  Google Scholar 

  13. Graf, G.A. et al. ABCG5 and ABCG8 are obligate heterodimers for protein trafficking and biliary cholesterol excretion. J. Biol. Chem. 278, 48275–48282 (2003).

    Article  CAS  Google Scholar 

  14. Yu, L. et al. Expression of ABCG5 and ABCG8 is required for regulation of biliary cholesterol secretion. J. Biol. Chem. 280, 8742–8747 (2005).

    Article  CAS  Google Scholar 

  15. Repa, J.J. et al. Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors α and β. J. Biol. Chem. 277, 18793–18800 (2002).

    Article  CAS  Google Scholar 

  16. Remaley, A.T. et al. Comparative genome analysis of potential regulatory elements in the ABCG5-ABCG8 gene cluster. Biochem. Biophys. Res. Commun. 295, 276–282 (2002).

    Article  CAS  Google Scholar 

  17. Foufelle, F. & Ferre, P. New perspectives in the regulation of hepatic glycolytic and lipogenic genes by insulin and glucose: a role for the transcription factor sterol regulatory element binding protein-1c. Biochem. J. 366, 377–391 (2002).

    Article  CAS  Google Scholar 

  18. Zhang, W. et al. FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression. J. Biol. Chem. 281, 10105–10117 (2006).

    Article  CAS  Google Scholar 

  19. Kodama, S., Koike, C., Negishi, M. & Yamamoto, Y. Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes. Mol. Cell. Biol. 24, 7931–7940 (2004).

    Article  CAS  Google Scholar 

  20. Jiang, Z.Y. et al. Increased expression of LXRα, ABCG5, ABCG8 and SR-BI in the liver from normolipidemic, nonobese Chinese gallstone patients. J. Lipid Res. 49, 464–472 (2008).

    Article  CAS  Google Scholar 

  21. Uppal, H. et al. Activation of liver X receptor sensitizes mice to gallbladder cholesterol crystallization. Hepatology 47, 1331–1342 (2008).

    Article  CAS  Google Scholar 

  22. Akiyoshi, T., Uchida, K., Takase, H., Nomura, Y. & Takeuchi, N. Cholesterol gallstones in alloxan-diabetic mice. J. Lipid Res. 27, 915–924 (1986).

    CAS  PubMed  Google Scholar 

  23. Shaffer, E.A. & Small, D.M. Biliary lipid secretion in cholesterol gallstone disease. The effect of cholecystectomy and obesity. J. Clin. Invest. 59, 828–840 (1977).

    Article  CAS  Google Scholar 

  24. Bennion, L.J. & Grundy, S.M. Effects of obesity and caloric intake on biliary lipid metabolism in man. J. Clin. Invest. 56, 996–1011 (1975).

    Article  CAS  Google Scholar 

  25. Ishida, H., Yamashita, C., Kuruta, Y., Yoshida, Y. & Noshiro, M. Insulin is a dominant suppressor of sterol 12 α-hydroxylase P450 (CYP8B) expression in rat liver: possible role of insulin in circadian rhythm of CYP8B. J. Biochem. 127, 57–64 (2000).

    Article  CAS  Google Scholar 

  26. Carey, M.C. & Leonard, M.R. Pathophysiology of bile secretion. in Future Perspectives in Gastroenterology Falk Sym. Vol. 161 (eds. Carey, M.C., Díte, P., Gabryelewicz, A., Keim, V. & Mössner, J.) 77–96 (Springer, Heidelberg, in the press).

  27. Grundy, S.M., Lan, S.P. & Lachin, J. The effects of chenodiol on biliary lipids and their association with gallstone dissolution in the National Cooperative Gallstone Study (NCGS). J. Clin. Invest. 73, 1156–1166 (1984).

    Article  CAS  Google Scholar 

  28. Attili, A.F. et al. Factors associated with gallstone disease in the MICOL experience. Multicenter Italian Study on Epidemiology of Cholelithiasis. Hepatology 26, 809–818 (1997).

    Article  CAS  Google Scholar 

  29. Biddinger, S.B. et al. Effects of diet and genetic background on sterol regulatory element-binding protein-1c, stearoyl-CoA desaturase 1, and the development of the metabolic syndrome. Diabetes 54, 1314–1323 (2005).

    Article  CAS  Google Scholar 

  30. Yu, L. et al. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc. Natl. Acad. Sci. USA 99, 16237–16242 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank C. Rask-Madsen for photography and M. Leonard and D. Cohen for helpful discussions. We also thank H. Hobbs (University of Texas Southwestern Medical Center at Dallas) for antibodies to ABCG5 and ABCG8, T. Willson (GlaxoSmithKline) for supplying GW4064 and J. Sakai (University of Tokyo) for the ABCG5 and ABCG8 luciferase reporter constructs. This work was funded in part by grants from the US National Institutes of Health, including DK063696-05 (S.B.B.), DK31036 and DK45935 (C.R.K.), DK036588 and DK073687 (M.C.C.), the Joslin Diabetes and Endocrine Research Center grant DK036836-20 and the Veterans Affairs Merit Review Program (T.G.U.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sudha B Biddinger.

Supplementary information

Supplementary Text and Figures

Supplementary Fig. 1, Supplementary Tables 1–4 and Supplementary Methods (PDF 203 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Biddinger, S., Haas, J., Yu, B. et al. Hepatic insulin resistance directly promotes formation of cholesterol gallstones. Nat Med 14, 778–782 (2008). https://doi.org/10.1038/nm1785

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1785

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing